Mechanical ventilation with high tidal volume or frequency is associated with increased expression of nerve growth factor and its receptor in rabbit lungs.

OBJECTIVE: Nerve growth factor (NGF), a neurotrophin, is induced in lung cells by proinflammatory cytokines, and has a role in bronchial hyperreactivity and lung tissue repair. Ventilation induced lung injury, on the other hand, is known to increase the levels of proinflammatory cytokines in the lungs. We investigated whether, and to what extent, various degrees of lung injury induced by short-term ventilation affect NGF levels in the lung tissue of adolescent rabbits. METHODS: The rabbits were randomized to different modes of ventilation: (1) CON: normal ventilation for 30 min; (2) NVT: normal ventilation for 6 hr; (3) HFQ: ventilation for 6 hr at double frequency, but normal tidal volume (VT); and (4) HVT: 6 hr ventilation at double VT but normal frequency. RESULTS: NGF protein was detected in bronchoalveolar lavage fluid (BALF) and lung tissue in all animals. Ventilation for 6 hr significantly increased NGF levels, in both BALF and lung tissue, in the HFQ and HVT groups as compared to control (P < 0.05). The maximum increase in BALF NGF was seen in the HVT group (P = 0.02 vs. CON and NVT groups, and P = 0.05 vs. HFQ). A parallel increase in interleukin 1-beta (IL1-beta) was observed. Expression of the high-affinity NGF-receptor, tropomyosin-related kinase A (TrkA), was also upregulated in these two groups. CONCLUSION: Injurious modes of mechanical ventilation upregulate NGF and its receptor TrkA in rabbit lungs, and IL1-beta may be a mediator for this response. We speculate that this increase in NGF level may translate into the development of bronchial hyperreactivity.

Effects of duration and amount of lung stretch at biophysical, biochemical, histological, and transcriptional levels in an in vivo rabbit model of mild lung injury.

The purpose of this study was to characterize the effects of doubling minute ventilation (either by doubling ventilator frequency [Freq] or tidal volume [V T]) and of normal minute ventilation prolonged to 12-fold duration, synchronously at biophysical, biochemical/cellular, histological, and transcriptional levels in a model of mild lung injury. A prospective, randomized study was performed on adolescent New-Zealand white rabbits. The rabbits were randomly assigned to one of the following groups: control (normal minute ventilation for 0.5 hours); 1 x V T, 12-fold prolongation at normal V T (normal minute ventilation for 6 hours [12 x 0.5 hours]); 2 x Freq at normal V T (double minute ventilation for 6 hours); and 2 x V T at normal Freq (double minute ventilation for 6 hours). Normocapnia was maintained throughout the experiment. At the biophysical level, gas exchange (alveolar-arterial O2-tension difference [ AaDO2]) deteriorated by 23, 51, and 95%, and respiratory compliance decreased by 6.0, 18.4, and 26% in the 1 x V T, 2 x Freq, and 2 x V T group, respectively, during 6 hours of ventilation. Concomitantly, at the biochemical-cellular level, interleukin-8 (IL-8) in the bronchoalveolar lavage fluid increased 44-fold, 150-fold, and 275-fold ( P = 0.02), respectively. The white blood cell count decreased significantly in all three intervention groups. At the histological level, the influx of leukocytes as well as the tissue water content increased in proportion to the degree of injury. At the transcriptional level, lung IL-8 mRNA expression increased 11-fold in the 2 x V T group ( P = 0.002), 9-fold ( P = 0.02) in the 2 x Freq group, and 4-fold in the 1 x V T group as compared with control. Not only doubling V T, but also doubling Freq at normal V T injures the lung significantly, although to a lesser extent. A concept of weighted risk for increases of V T and Freq is proposed.